Essential hypertension is extremely prevalent in the population, and a significant percentage of these patients manifest salt-sensitive hypertension. Although the etiology of salt-sensitive hypertension is undoubtedly multifactorial, there is experimental and epidemiologic evidence linking abnormalities in the cyclooxygenase (COX)/prostaglandin system to pathogenesis. COX-2 inhibitors, as well as non-selective non- steroidal anti-inflammatory drugs (NSAIDs) are known to elevate blood pressure (BP) and antagonize the BP- lowering effect of antihypertensive medication in many users. NSAIDs and COX-2 inhibitors can also induce peripheral edema in certain patients. Selective inhibition of COX-2 has been implicated in increased cardiovascular mortality, which appears to be multifactorial, and may involve increases in BP and salt and water retention Thus, COX-2 activity seems to be an important mediator of salt and water homeostasis and a guard against development of salt-sensitive hypertension. The mechanism by which COX-2 inhibition leads to development or exacerbation of salt-sensitive hypertension has been generally thought to be due primarily to inhibition of intrinsic renal COX-2 activity, since salt loading up-regulates COX- expression in renal medulla, and COX-2 inhibitors reduce urinary sodium excretion. However, we have found that transplanting bone marrow from mice deficient in COX-2 or the major prostaglandin E2 synthase associated with COX-2 (mPGES- 1) into wild type mice leads to the development of salt-sensitive hypertension. These findings indicate that previous paradigms about the development of salt-sensitive hypertension are incomplete. More importantly, these findings suggest a completely novel and unexplored role for COX-2 generated prostaglandins from bone marrow-derived cells in regulation of blood pressure homeostasis as well as salt and water regulation. These observations suggest that COX-2 metabolites generated from bone marrow-derived cells may partner with COX-2 metabolites from intrinsic renal cells to prevent development of salt-sensitive hypertension. As a corollary, we will also test whether inhibition of COX-2 metabolites specifically from bone marrow-derived cells is a central factor in NSAID-mediated hypertension and edema. To investigate underlying mechanisms of this novel role of bone marrow-derived COX-2 in regulation of blood pressure, we have developed three specific aims: Specific Aim #1 will determine the role of prostaglandins generated from COX-2 expression in eitherbone marrow-derived cells in regulation of salt and water homeostasis; specific aim #2 will determine mechanism(s) by which COX-2 generated prostaglandins from bone marrow-derived bells mediate salt- sensitive hypertension. Aim #3 will examine underlying mechanisms by which COX-2 inhibition can predispose to development of peripheral edema. In summary, these studies will test a novel and innovative hypothesis concerning the underlying mechanisms of hypertension.